title: Benzazepinones and benzoxazepinones as antagonists of inhibitor of apoptosis proteins (IAPs) selective for the second baculovirus IAP repeat (BIR2) domain.
abstract: XIAP is a key regulator of apoptosis, and its overexpression in cancer cells may contribute to their survival. The antiapoptotic function of XIAP derives from its BIR domains, which bind to and inhibit pro-apoptotic caspases. Most known IAP inhibitors are selective for the BIR3 domain and bind to cIAP1 and cIAP2 as well as XIAP. Pathways activated upon cIAP binding contribute to the function of these compounds. Inhibitors selective for XIAP should exert pro-apoptotic effects through competition with the terminal caspases. This paper details our synthetic explorations of a novel XIAP BIR2-selective benzazepinone screening hit with a focus on increasing BIR2 potency and overcoming high in vivo clearance. These efforts led to the discovery of benzoxazepinone 40, a potent BIR2-selective inhibitor with good in vivo pharmacokinetic properties which potentiates apoptotic signaling in a manner mechanistically distinct from that of known pan-IAP inhibitors.
authors.affiliation: Departments of Discovery Chemistry, ‡Discovery Technologies, §Non-clinical Safety, Early ADME, and ∥Discovery Oncology, Hoffmann-La Roche Inc. , 340 Kingsland Street, Nutley, New Jersey 07110, United States.
authors.forename: Andrew F
authors.initials: AF
authors.lastname: Donnell
authors.forename: Christophe
authors.initials: C
authors.lastname: Michoud
authors.forename: Kenneth C
authors.initials: KC
authors.lastname: Rupert
authors.forename: Xiaochun
authors.initials: X
authors.lastname: Han
authors.forename: Douglas
authors.initials: D
authors.lastname: Aguilar
authors.forename: Karl B
authors.initials: KB
authors.lastname: Frank
authors.forename: Adrian J
authors.initials: AJ
authors.lastname: Fretland
authors.forename: Lin
authors.initials: L
authors.lastname: Gao
authors.forename: Barry
authors.initials: B
authors.lastname: Goggin
authors.forename: J Heather
authors.initials: JH
authors.lastname: Hogg
authors.forename: Kyoungja
authors.initials: K
authors.lastname: Hong
authors.forename: Cheryl A
authors.initials: CA
authors.lastname: Janson
authors.forename: Robert F
authors.initials: RF
authors.lastname: Kester
authors.forename: Norman
authors.initials: N
authors.lastname: Kong
authors.forename: Kang
authors.initials: K
authors.lastname: Le
authors.forename: Shirley
authors.initials: S
authors.lastname: Li
authors.forename: Weiling
authors.initials: W
authors.lastname: Liang
authors.forename: Louis J
authors.initials: LJ
authors.lastname: Lombardo
authors.forename: Yan
authors.initials: Y
authors.lastname: Lou
authors.forename: Christine M
authors.initials: CM
authors.lastname: Lukacs
authors.forename: Steven
authors.initials: S
authors.lastname: Mischke
authors.forename: John A
authors.initials: JA
authors.lastname: Moliterni
authors.forename: Ann
authors.initials: A
authors.lastname: Polonskaia
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Schutt
authors.forename: Dave S
authors.initials: DS
authors.lastname: Solis
authors.forename: Anthony
authors.initials: A
authors.lastname: Specian
authors.forename: Robert T
authors.initials: RT
authors.lastname: Taylor
authors.forename: Martin
authors.initials: M
authors.lastname: Weisel
authors.forename: Stacy W
authors.initials: SW
authors.lastname: Remiszewski
mesh_terms: D000409:Alanine / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D018360:Crystallography, X-Ray; D005260:Female; D006571:Heterocyclic Compounds / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D008956:Models, Chemical; D008958:Models, Molecular; D015394:Molecular Structure; D010077:Oxazepines / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D051381:Rats; D044767:Ubiquitin-Protein Ligases; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D006571:Heterocyclic Compounds; D051034:Inhibitor of Apoptosis Proteins; C586832:N-(5-((2-cyano-1-(2-cyanophenyl)-1H-indol-3-yl)methyl)-4-oxo-2',3',4,5,5',6'-hexahydro-3H-spiro(benzo(b)(1,4)oxazepine-2,4'-pyran)-3-yl)-2-(methylamino)propanamide; D010077:Oxazepines; D051636:X-Linked Inhibitor of Apoptosis Protein; C554537:conatumumab; C494833:BIRC2 protein, human; D044767:Ubiquitin-Protein Ligases; D053148:Caspase 3; D053179:Caspase 7; D000409:Alanine